The Role Of MEKK2 In Promoting Gut Epithelium Repair

Proper intestinal repair is essential for the maintenance of gut integrity and homeostasis.Multiple signals including those induced by the agonists of Wnt,Notch,BMP and other growth factors,cytokines and inflammation signals are critically important for this process.However,the precise cellular signaling mechanisms that control certain agonists production in intestine upon tissue regeneration or reorganization remain to be fully revealed.In this study,we show that mitogen-activated protein kinase(MAPK)kinase kinase 2,also known as MEKK2,plays an CD90+ stromal cells specific role in inducing R-spondin-1 production in response to acute damage.Genetic ablation of MEKK2 results in much severe colitis in response to DSS-induced intestine damage as evidenced by more infiltration of inflammatory cells,highly reduced number of goblet cells and a great loss of LGR5+intestine stem cells.But MEKK2 is not required for intestinal stem cell proliferation and differentiation in vitro.Using bone marrow transplant experiments,we revealed that MEKK2 has a specific role in the non-hematopoietic cells,which is critical in protection of mouse gut from the DSS-induced damage.From high-throughput sequencing data,we found that MEKK2 is essential for the production of Wnt agonist R-spondin1 by the intestinal CD90+ stromal cells upon damage,thus upregulating the regeneration signals in the intestine stem cell niche to promote gut epithelial differentiation for the repair.Further study indicated ROS signaling activates MEKK2-ERK5 and promotes KLF2 expression.KLF2 can enhance R-spondin1 production by binding to the promotor region of Rspo1.Together,our study revealed an important and specific role of MEKK2 in maintaining gut homeostasis,and provided scientific basis for clinic treatment.